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Genetic control of scrapie and Creutzfeldt-Jakob disease in mice
Abstract:
Genetic control of experimental scrapie and Creutzfeldt-Jakob disease (CJD) was studied in inbred strains of mice by measuring the times from intracerebral inoculation with the agents to the onset of neurological dysfunction. Every strain of mice examined was susceptible to infection; however, a wide range of incubation times was found for both scrapie and CJD. New Zealand (NZ) mice, which eventually develop an autoimmune disorder, were inoculated intracerebrally with 10(6) ID50 units of the scrapie agent in a Chandler isolate. NZW mice showed incubation periods of less than 95 days; this is the shortest period recorded for any murine host with scrapie. In NZB and NZB X W F1 mice, the incubation periods were approximately 130 days and were similar to those in BALB/c and C57BL mice. Male and female NZ mice exhibited scrapie incubation periods of the same length. Similar results were obtained when B10.Q and C57BL/6J mice were inoculated intracerebrally with 10(4) ID50 units of the CJD agent in a K.Fu. isolate. These observations define a genetic locus or loci controlling the length of scrapie and CJD incubation periods; alleles coding for longer incubation times appear to be autosomal dominant. When congenic mice with a C57BL/10J background differing only in their H-2 haplotypes were studied, the results showed that the D subregion of the H-2 complex played a central role in controlling the length of the CJD incubation period. The q allele at the D subregion resulted in shorter incubation times, whereas the d allele resulted in long incubation times. The p, s, b, and k alleles gave intermediate incubation times. We propose the symbol PID-1 for designating this genetic locus which is located within the D subregion of the major histocompatibility (H-2) complex on murine chromosome 17. In addition, observations on congenic mice provide evidence for the influence of sex on CJD incubation periods. In some strains of inbred mice, males showed significantly shorter incubation periods compared with those for females with experimental CJD. These studies with inbred mice have defined previously unrecognized genes that control the length of scrapie and CJD incubation periods.
Insights
Researchers identified genetic factors controlling incubation periods for scrapie and Creutzfeldt-Jakob disease (CJD) in mice. A specific gene locus, PID-1, within the H-2 complex significantly influences disease onset, with implications for understanding prion disease genetics.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Scrapie and Creutzfeldt-Jakob disease (CJD) are transmissible spongiform encephalopathies.
- Genetic factors are known to influence disease susceptibility and incubation periods.
Purpose of the Study:
- To investigate the genetic control of incubation times for experimental scrapie and CJD in inbred mouse strains.
- To identify specific genetic loci and their influence on prion disease progression.
Main Methods:
- Intracerebral inoculation of mice with scrapie and CJD agents.
- Measurement of incubation periods from inoculation to neurological dysfunction onset.
- Analysis of incubation times in various inbred and congenic mouse strains with different H-2 haplotypes.
Main Results:
- All mouse strains were susceptible, but incubation periods varied widely.
- A major genetic locus, PID-1, located in the D subregion of the H-2 complex on chromosome 17, significantly controls CJD incubation time.
- Specific alleles (q vs. d) at the H-2 D subregion determined shorter or longer incubation periods, respectively.
- Sex influenced CJD incubation periods in some mouse strains, with males exhibiting shorter times.
Conclusions:
- Genetic control of scrapie and CJD incubation periods is complex, involving at least one major locus (PID-1).
- The H-2 complex, particularly the D subregion, plays a crucial role in modulating CJD incubation periods.
- These findings reveal previously unrecognized genes influencing prion disease incubation times in mice.